This invention relates generally to inhibitors of trypsin-like serine protease enzymes, especially factor Xa or thrombin, pharmaceutical compositions containing the same, and methods of using the same as anticoagulant agents for treatment and prevention of thromboembolic disorders.
Activated factor Xa, whose major practical role is the generation of thrombin by the limited proteolysis of prothrombin, holds a central position that links the intrinsic and extrinsic activation mechanisms in the final common pathway of blood coagulation. The generation of thrombin, the final serine protease in the pathway to generate a fibrin clot, from its precursor is amplified by formation of prothrombinase complex (factor Xa, factor V, Ca2+ and phospholipid). Since it is calculated that one molecule of factor Xa can generate 138 molecules of thrombin (Elodi, S., Varadi, K.: Optimization of conditions for the catalytic effect of the factor IXa-factor VIII Complex: Probable role of the complex in the amplification of blood coagulation. Thromb. Res. 1979, 15, 617-629), inhibition of factor Xa may be more efficient than inactivation of thrombin in interrupting the blood coagulation system.
Therefore, efficacious and specific inhibitors of factor Xa, thrombin, or both are needed as potentially valuable therapeutic agents for the treatment of thromboembolic disorders. It is thus desirable to discover new factor Xa, thrombin, or both inhibitors.
Accordingly, one object of the present invention is to provide novel nitrogen containing aromatic heterocycles, with ortho-substituted P1 groups, which are useful as factor Xa inhibitors or pharmaceutically acceptable salts or prodrug thereof.
It is another object of the present invention to provide pharmaceutical compositions comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of at least one of the compounds of the present invention or a pharmaceutically acceptable salt or prodrug form thereof.
It is another object of the present invention to provide a method for treating thromboembolic disorders comprising administering to a host in need of such treatment a therapeutically effective amount of at least one of the compounds of the present invention or a pharmaceutically acceptable salt or prodrug form thereof.
It is another object of the present invention to provide novel compounds for use in therapy.
It is another object of the present invention to provide the use of novel compounds for the manufacture of a medicament for the treatment of thrombosis or a disease mediated by factor Xa.
[1] Thus, in a first embodiment, the present invention provides a novel compound selected from the group: 
or a stereoisomer or pharmaceutically acceptable salt thereof, wherein;
G is selected from the group: 
Ln is a linker which is absent or is selected from O, S, CH2, *CH2NHC(O), *CH(Ra)NHC(O), *CH2NHC(O)CH2, and *CH(Ra)NHC(O)CH2, provided that Ln and M do not form an Oxe2x80x94N or Sxe2x80x94N bond and the * indicates where Ln is bonded to G;
M1 is absent or is CHR;
M2 is N or CRf;
M3 is N or CRd;
provided that only one of M2 and M3 is N;
Ra is selected from C(O)C(O)OR3, C(O)C(O)NR2R2a, and C(O)-A;
Rb is selected from H, R, phenyl, C1-10 alkyl, and C2-5 alkenyl;
Rc is selected from H and C1-6 alkyl;
alternatively, Rb and Rc together are xe2x80x94(CH2)4xe2x80x94;
Rd is selected from H, F, and Cl;
Re is selected from H, N(CH3) (CH2CO2H) and S-(5-6 membered aromatic heterocyclic system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-2 R4);
alternatively, Rd and Re combine to form xe2x80x94NR3xe2x80x94C(O)xe2x80x94C(R1bR3)xe2x80x94NR3xe2x80x94 or xe2x80x94Nxe2x95x90CR2xe2x80x94NR3xe2x80x94;
Rf is selected from H, F, and Cl;
alternatively, Re and Rf combine to form xe2x80x94NR3xe2x80x94C(R1bR3)xe2x80x94C(O)xe2x80x94NR3xe2x80x94 or xe2x80x94NR3xe2x80x94CR2xe2x95x90Nxe2x80x94;
Rg is selected from H, CH2OR3, CH2C(O)OR3, C1-4 alkyl, C(O)NH2, and NH2;
Rh is selected from H, CH2-phenyl, CH2CH2-phenyl, and CHxe2x95x90CH-phenyl;
Ri is selected from SO2CH2C(O)OR3, C(O)CH2C(O)OR3, and C(O)OR3;
R is selected from H, Cl, F, Br, I, (CH2)tOR3, C1-4 alkyl, benzyl, OCF3, CF3, C(O)NR7R8, and (CR8R9)tNR7R8;
Z is selected from (CR8R9)1-4, (CR8R9)rO (CR8R9)r, (CR8R9)rNR3(CR8R9)r, (CR8R9)rC(O) (CR8R9)r, (CR8R9)rC(O)O(CR8R9)r, (CR8R9)rOC(O)(CR8R9)r, (CR8R9)rC(O)NR3(CR8R9)r, (CR8R9)rNR3C(O)(CR8R9)r, (CR8R9)rOC(O)O(CR8R9)r, (CH2)rOC(O)NR3(CR8R9)r, (CR8R9)rNR3C(O)O(CR8R9)r, (CH2)rNR3C(O)NR3(CR8R9)r, (CR8R9)rS(O)p(CR8R9)r, (CR8R9)rS(O)2(CHxe2x95x90CH), (CCR8R9)rSO2NR3 (CR8R9)r, (CR8R9)rNR3SO2 (CR8R9)r, and (CR8R9)rNR3SO2NR3(CR8R9)r, provided that Z does not form a Nxe2x80x94N, Nxe2x80x94O, Nxe2x80x94S, NCH2N, NCH2O, or NCH2S bond with the groups to which Z is attached;
R1a is absent or selected from xe2x80x94(CH2)rxe2x80x94R1xe2x80x2, xe2x80x94CHxe2x95x90CHxe2x80x94R1xe2x80x2, NHCH2R1xe2x80x3, OCH2R1xe2x80x3, SCH2R1xe2x80x3, NH(CH2)2(CH2)tR1xe2x80x2, O(CH2)2(CH2)tR1xe2x80x2, and S(CH2)2(CH2)tR1xe2x80x2;
R1xe2x80x2 is selected from H, C1-3 alkyl, F, Cl, Er, I, xe2x80x94CN, xe2x80x94CHO, (CF2)rCF3, (CH2)rOR2, NR2R2a, C(O)R2c, OC(O)R2, (CF2)rCO2R2c, S(O)p(CH2)rR2b, NR2(CH2)rOR2, C(xe2x95x90NR2c)NR2R2a, NR2C(O)R2b, NR2C(O)NHR2b, NR2C(O)2R2a, OC(O)NR2aR2b, C(O)NR2R2a, C(O)NR2(CH2)rOR2, SO2NR2R2a, NR2SO2R2b, C3-6 carbocyclic residue substituted with 0-2 R4, and 5-10 membered heterocyclic system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-2 R4;
R1xe2x80x3 is selected from H, CH(CH2OR2)2, C(O)R2c, C(O)NR2R2a, S(O)R2b, S(O)2R2b, and SO2NR2R2a;
R1b is selected from H, C1-6 alkyl, and C1-6 alkyl substituted with A;
R2, at each occurrence, is selected from H, CF3, C1-6 alkyl, benzyl, C3-6 carbocyclic residue substituted with 0-2 R4b, and 5-6 membered heterocyclic system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-2 R4b;
R2a, at each occurrence, is selected from H, CF3, C1-6 alkyl, benzyl, C3-6 cycloalkylmethyl substituted with 0-2 R4b, C3-6 carbocyclic residue substituted with 0-2 R4b, and 5-6 membered heterocyclic system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-2 R4b;
R2b, at each occurrence, is selected from CF3, C1-4 alkoxy, C1-6 alkyl, benzyl, C3-6 carbocyclic residue substituted with 0-2 R4b, and 5-6 membered heterocyclic system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-2 R4b;
R2c, at each occurrence, is selected from CF3, OH, C1-4 alkoxy, C1-6 alkyl, benzyl, C3-6 carbocyclic residue substituted with 0-2 R4b, and 5-6 membered heterocyclic system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-2 R4b;
alternatively, R2 and R2a, together with the atom to which they are attached, combine to form a 5 or 6 membered saturated, partially saturated or unsaturated ring substituted with 0-2 R4b and containing from 0-1 additional heteroatoms selected from the group consisting of N, O, and S;
R3, at each occurrence, is selected from H, C1-4 alkyl, and phenyl;
R3a, at each occurrence, is selected from H, C1-4 alkyl, and phenyl;
R3b, at each occurrence, is selected from H, C1-4 alkyl, and phenyl;
R3c, at each occurrence, is selected from C1-4 alkyl, and phenyl;
A is selected from:
C3-10 carbocyclic residue substituted with 0-2 R4, and
5-10 membered heterocyclic system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-2 R4;
A1 is H or A;
alternatively, A and A1 and the carbon to which they are attached combine to form fluorene;
A2 is selected from H, A, and CHA3A4;
A3 is selected from H, A, C1-4 alkyl, and xe2x80x94(CH2)rNR2R2a;
A4 is H or A;
B is selected from: H, Y, and Xxe2x80x94Y
X is selected from C1-4 alkylene, xe2x80x94CR2(CR2R2b)(CH2)txe2x80x94, xe2x80x94C(O)xe2x80x94, xe2x80x94CR2(NR1xe2x80x3R2)xe2x80x94, xe2x80x94CR2(OR2)xe2x80x94, xe2x80x94CR2(SR2)xe2x80x94, xe2x80x94C(O)CR2R2axe2x80x94, xe2x80x94CR2R2aC(O), xe2x80x94OS(O)2xe2x80x94, xe2x80x94S(O)pxe2x80x94, xe2x80x94S(O)pCR2R2axe2x80x94, xe2x80x94CR2R2aS(O)pxe2x80x94, xe2x80x94S(O)2NR2xe2x80x94, xe2x80x94NR2S(O)2xe2x80x94, xe2x80x94NR2S(O)2CR2R2axe2x80x94, xe2x80x94CR2R2aS(O)2NR2xe2x80x94, xe2x80x94NR2S(O)2NR2xe2x80x94, xe2x80x94C(O)NR2xe2x80x94, xe2x80x94NR2C(O)xe2x80x94, xe2x80x94C(O)NR2CR2R2axe2x80x94, xe2x80x94NR2C(O)CR2R2axe2x80x94, xe2x80x94CR2R2aC(O)NR2xe2x80x94, xe2x80x94CR2R2aNR2C(O)xe2x80x94, xe2x80x94NR2C(O)Oxe2x80x94, xe2x80x94OC(O)NR2xe2x80x94, xe2x80x94NR2C(O)NR2xe2x80x94, xe2x80x94NR2xe2x80x94, xe2x80x94NR2CR2R2axe2x80x94, CR2R2aNR2xe2x80x94, O, xe2x80x94CR2R2aOxe2x80x94, and xe2x80x94OCR2R2axe2x80x94;
Y is selected from:
(CH2)rNR2R2a, provided that Xxe2x80x94Y do not form a Nxe2x80x94N, Oxe2x80x94N,
or Sxe2x80x94N bond,
C3-10 carbocyclic residue substituted with 0-2 R4a, and
5-10 membered heterocyclic system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-2 R4a;
alternatively, Z-A-B combine to form Sxe2x80x94C1-6 alkyl;
R4, at each occurrence, is selected from H, xe2x95x90O, (CH2)rOR2, F, Cl, Br, I, C1-4 alkyl, xe2x80x94CN, NO2, (CH2)rNR2R2a, (CH2)rC(O)R2c, NR2C(O)R2b, C(O)NR2R2a, NR2C(O)NR2R2a, C(xe2x95x90N2)NR2R2a, C(xe2x95x90NS(O)2R5)NR2R2a, NHC(xe2x95x90NR2)NR2R2a, C(O)NHC(xe2x95x90NR2)NR2R2a, SO2NR2R2a, NR2SO2NR2R2a, NR2SO2xe2x80x94C1-4 alkyl, NR2SO2R5, S(O)pR5, (CF2)rCF3, NHCH2R1xe2x80x3, OCH2R1xe2x80x3, SCH2R1xe2x80x3, N(CH2)2(CH2)tR1xe2x80x2, O(CH2)2(CH2)tR1xe2x80x2, and S(CH2)2(CH2)tR1xe2x80x3;
alternatively, one R4 is a 5-6 membered aromatic heterocycle containing from 1-4 heteroatoms selected from the group consisting of N, O, and S;
R4a, at each occurrence, is selected from H, xe2x95x90O, (CH2)rOR2, (CH2)rxe2x80x94F, (CH2)rxe2x80x94Br, (CH2)rxe2x80x94Cl, Cl, Br, F, I, C1-4 alkyl, xe2x80x94CN, NO2, (CH2)rNR2R2a, (CH2)rC(O)R2c, NR2C(O)R2b, C(O)NR2R2a, C(O)NH(CH2)2NR2R2a, NR2C(O)NR2R2a, C(xe2x95x90NR2)R3c, C(xe2x95x90NR2) NR2R2a, NHC(xe2x95x90NR2)NR2R2a, SO2NR2R2a, NR2SO2NR2a, NR2SO2xe2x80x94C1-4 alkyl, C(O)NHSO2xe2x80x94C1-4 alkyl, NR2SO2R5, S(O)pR5, and (CF2)rCF3;
alternatively, one R4a is a 5-6 membered aromatic heterocycle containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-1 R5;
R4b, at each occurrence, is selected from H, xe2x95x90O, (CH2)rOR3, F, Cl, Br, I, C1-4 alkyl, xe2x80x94CN, NO2, (CH2)rNR3R3a, (CH2)rC(O)R3, (CH2)rC(O)OR3c, NR3C(O)R3a, C(O)NR3R3a, NR3C(O)NR3R3a, C(xe2x95x90NR3)NR3R3a, NR3C(xe2x95x90NR3)NR3R3a, SO2NR3R3a, NR3SO2NR3R3a, NR3SO2xe2x80x94C1-4 alkyl, NR3SO2CF3, NR3SO2-phenyl, S(O)pCF3, S(O)pxe2x80x94C1-4 alkyl, S(O)p-phenyl, and (CF2)rCF3;
R5, at each occurrence, is selected from CF3, C1-6 alkyl, phenyl substituted with 0-2 R6, and benzyl substituted with 0-2 R6;
R6, at each occurrence, is selected from H, OH, (CH2)rOR2, halo, C1-4 alkyl, CN, NO2, (CH2)rNR2R2a, (CH2)rC(O)R2b, NR2C(O)R2b, NR2C(O)NR2R2a, C(xe2x95x90NH)NH2, NHC(xe2x95x90NH)NH2, SO2NR2R2a, NR2SO2NR2R2a, and NR2SO2C1-4 alkyl;
R7, at each occurrence, is selected from H, OH, C1-6 alkyl, C1-6 alkylcarbonyl, C1-6 alkoxy, C1-4 alkoxycarbonyl, (CH2)n-phenyl, C6-10 aryloxy, C6-10 aryloxycarbonyl, C6-10 arylmethylcarbonyl, C1-4 alkylcarbonyloxy C1-4 alkoxycarbonyl, C6-10 arylcarbonyloxy C1-4 alkoxycarbonyl, C1-6 alkylaminocarbonyl, phenylaminocarbonyl, and phenyl C1-4 alkoxycarbonyl;
R8, at each occurrence, is selected from H, C1-6 alkyl and (CH2)n-phenyl;
alternatively, R7 and R8 combine to form a 5 or 6 membered saturated, ring which contains from 0-1 additional heteroatoms selected from the group consisting of N, O, and S;
R9, at each occurrence, is selected from H, C1-6 alkyl and (CH2)n-phenyl;
n, at each occurrence, is selected from 0, 1, 2, and 3;
m, at each occurrence, is selected from 0, 1, and 2;
p, at each occurrence, is selected from 0, 1, and 2;
r, at each occurrence, is selected from 0, 1, 2, and 3;
s, at each occurrence, is selected from 0, 1, and 2; and,
t, at each occurrence, is selected from 0, 1, 2, and 3.
[2] In a preferred embodiment, the present invention provides a novel compound, wherein:
G is selected from the group: 
[3] In a more preferred embodiment, the present invention provides a novel compound, wherein:
G is selected from: 
[4] In an even more preferred embodiment, the present invention provides a novel compound, wherein:
R is selected from H, Cl, F, Br, I, (CH2)tOR3, C1-4 alkyl, OCF3, CF3, C(O)NR7R8, and (CR8R9)tNR7R8;
Z is selected from CH2O, OCH2, CH2NH, NHCH2, C(O), CH2C(O), C(O)CH2, NHC(O), C(O)NH, CH2S(O)2, S(O)2(CH2), SO2NH, and NHSO2, provided that Z does not form a Nxe2x80x94N, Nxe2x80x94O, NCH2N, or NCH2O bond with ring M or group A;
A is selected from one of the following carbocyclic and heterocyclic systems which are substituted with 0-2 R4;
phenyl, piperidinyl, piperazinyl, pyridyl, pyrimidyl, furanyl, morpholinyl, thiophenyl, pyrrolyl, pyrrolidinyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, imidazolyl, oxadiazolyl, thiadiazolyl, triazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl, benzofuranyl, benzothiofuranyl, indolyl, benzimidazolyl, benzoxazolyl, benzthiazolyl, indazolyl, benzisoxazolyl, benzisothiazolyl, and isoindazolyl;
B is selected from: H, Y, and Xxe2x80x94Y;
X is selected from C1-4 alkylene, xe2x80x94C(O)xe2x80x94, xe2x80x94C(xe2x95x90NR)xe2x80x94, xe2x80x94CR2(NR2R2a)xe2x80x94, xe2x80x94C(O)CR2R2axe2x80x94, xe2x80x94CR2R2aC(O), xe2x80x94C(O)NR2xe2x80x94, xe2x80x94NR2C(O)xe2x80x94, xe2x80x94C(O)NR2CR2R2axe2x80x94, xe2x80x94NR2C(O)CR2R2axe2x80x94, xe2x80x94CR2R2aC(O)NR2xe2x80x94, xe2x80x94CR2R2aNR2C(O)xe2x80x94, xe2x80x94NR2C(O)NR2xe2x80x94, xe2x80x94NR2xe2x80x94, xe2x80x94NR2CR2R2axe2x80x94, xe2x80x94CR2R2aNR2xe2x80x94, O, xe2x80x94CR2R2aOxe2x80x94, and xe2x80x94OCR2R2axe2x80x94;
Y is NR2R2a or CH2NR2R2a, provided that Xxe2x80x94Y do not form a Nxe2x80x94N or Oxe2x80x94N bond;
alternatively, Y is selected from one of the following carbocyclic and heterocyclic systems which are substituted with 0-2 R4a;
cylcopropyl, cyclopentyl, cyclohexyl, phenyl, piperidinyl, piperazinyl, pyridyl, pyrimidyl, furanyl, morpholinyl, thiophenyl, pyrrolyl, pyrrolidinyl, oxazolyl, isoxazolyl, isoxazolinyl, thiazolyl, isothiazolyl, pyrazolyl, imidazolyl, oxadiazolyl, thiadiazolyl, triazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl, benzofuranyl, benzothiofuranyl, indolyl, benzimidazolyl, benzoxazolyl, benzthiazolyl, indazolyl, benzisoxazolyl, benzisothiazolyl, and isoindazolyl;
alternatively, Y is selected from the following bicyclic heteroaryl ring systems: 
K is selected from O, S, NH, and N.
[5] In a still more preferred embodiment, the present invention provides a novel compound, wherein:
Z is C(O)CH2 and CONH, provided that Z does not form a Nxe2x80x94N bond with group A;
A is selected from phenyl, pyridyl, and pyrimidyl, and is substituted with 0-2 R4; and,
B is selected from Y, Xxe2x80x94Y, phenyl, pyrrolidino, morpholino, 1,2,3-triazolyl, and imidazolyl, and is substituted with 0-1 R4a;
B is selected from: Y and Xxe2x80x94Y;
X is selected from CH2, xe2x80x94C(O)xe2x80x94, and O;
Y is NR2R2a or CH2NR2R2a, provided that Xxe2x80x94Y does not form an Oxe2x80x94N bond;
alternatively, Y is selected from one of the following carbocyclic and heterocyclic systems which are substituted with 0-2 R4a;
phenyl, piperazinyl, pyridyl, pyrimidyl, morpholinyl, pyrrolidinyl, imidazolyl, and 1,2,3-triazolyl;
R2, at each occurrence, is selected from H, CF3, CH3, benzyl, and phenyl;
R2a, at each occurrence, is selected from H, CF3, CH3, CH(CH3)2, cyclopropylmethyl, benzyl, and phenyl;
alternatively, R2 and R2a combine to form a ring system substituted with 0-2 R4b, the ring system being selected from pyrrolidinyl, piperazinyl and morpholino;
R4, at each occurrence, is selected from OH, (CH2)rOR2, Cl, F, C1-4 alkyl, (CH2)rNR2R2a, and (CF2)rCF3;
R4a is selected from Cl, F, C1-4 alkyl, CF3, (CH2)rNR2R2a, S(O)pR5, SO2NR2R2a, and 1-CF3-tetrazol-2-yl;
R4b, at each occurrence, is selected from OH, Cl, F, CH3, and CF3;
R5, at each occurrence, is selected from CF3, C1-6 alkyl, phenyl, and benzyl;
R7, at each occurrence, is selected from H, CH3, and CH2CH3; and,
R8, at each occurrence, is selected from H and CH3.
[6] In an even further preferred embodiment, the present invention provides a novel compound, wherein:
A is selected from the group: phenyl, 2-pyridyl, 3-pyridyl, 2-pyrimidyl, 2-Cl-phenyl, 3-Cl-phenyl, 2-F-phenyl, 3-F-phenyl 2-methylphenyl, 2-aminophenyl, and 2-methoxyphenyl; and,
B is selected from the group: 2-CF3-phenyl, 2-(aminosulfonyl)phenyl, 2-(methylaminosulfonyl)phenyl, 2-(dimethylaminosulfonyl)phenyl, 1-pyrrolidinocarbonyl, 2-(methylsulfonyl)phenyl, 2-(N,N-dimethylaminomethyl)phenyl, 2-(isopropylaminomethyl)phenyl, 2-(cyclopropylaminomethyl)phenyl, 2-(N-pyrrolidinylmethyl)phenyl, 2-(3-hydroxy-N-pyrrolidinylmethyl)phenyl, 4-morpholino, 2-(1xe2x80x2-CF3-tetrazol-2-yl)phenyl, 4-morpholinocarbonyl, 1-methyl-2-imidazolyl, 2-methyl-1-imidazolyl, 5-methyl-1-imidazolyl, 2-(N,N-dimethylaminomethyl)imidazolyl, 2-methylsulfonyl-1-imidazolyl and, 5-methyl-1,2,3-triazolyl.
[7] In another even more preferred embodiment, the present invention provides a compound of formula: 
Ln is *CH2NHC(O)CH2 or *CH(Ra)NHC(O)CH2, the * indicates where Ln is bonded to G;
Ra is C(O)C(O)OR3;
Z is selected from C1-4 alkylene, (CH2)rC(O), and (CH2)rS(O)2;
R2, at each occurrence, is selected from H, C1-6 alkyl, benzyl, and phenyl;
R2a, at each occurrence, is selected from H, C1-6 alkyl, benzyl, and phenyl;
R2b, at each occurrence, is selected from H, C1-6 alkyl, benzyl, and phenyl;
R2c, at each occurrence, is selected from OH, OCH3, OCH2CH3, CH3, benzyl, and phenyl;
R3, at each occurrence, is selected from H, C1-4 alkyl, and phenyl;
A is C5-6 carbocyclic residue substituted with 0-2 R4;
R4, at each occurrence, is selected from H, xe2x95x90O, (CH2)rOR2, F, Cl, Br, I, C1-4 alkyl, xe2x80x94CN, NO2, (CH2)rNR2R2a, (CH2)rC(O)R2c, NR2C(O)R2b, C(O)NR2R2a, C(xe2x95x90NR2)NR2R2a, NHC(xe2x95x90NR2)NR2R2a, SO2NR2R2a, S(O)pR5, and CF3;
R5, at each occurrence, is selected from CF3, C1-6 alkyl, phenyl, and benzyl;
p, at each occurrence, is selected from 0, 1, and 2; and,
r, at each occurrence, is selected from 0, 1, 2, and 3.
[8] In another still more preferred embodiment, the present invention provides a compound wherein:
Ln is *CH(Ra)NHC(O)CH2;
Ra is C(O)C(O)OH;
Z is selected from CH2, (CH2)2C(O), and CH2S(O)2;
A is cyclohexyl or phenyl and is substituted with 0-1 R4;
R4, at each occurrence, is selected from H, xe2x95x90O, OR2, CH2OR2, F, Cl, Br, I, C1-4 alkyl, xe2x80x94CN, NO2, (CH2)rNR2R2a, (CH2)rC(O)R2c, C(O)NR2R2a, SO2NR2R2a, and CF3; and,
r, at each occurrence, is selected from 0, 1, and 2.
[9] In another even more preferred embodiment, the present invention provides a compound of formula: 
Ln is *CH2NHC(O)CH2 or *CH(Ra)NHC(O)CH2, the * indicates where Ln is bonded to G;
Ra is C(O)C(O)OR3;
R is H or NH2;
Z is selected from C1-4 alkylene, (CH2)rC(O) and (CH2)rS(O)2;
R2, at each occurrence, is selected from H, C1-6 alkyl, benzyl, and phenyl;
R2a, at each occurrence, is selected from H, C1-6 alkyl, benzyl, and phenyl;
R2b, at each occurrence, is selected from H, C1-6 alkyl, benzyl, and phenyl;
R2c, at each occurrence, is selected from OH, OCH3, OCH2CH3, CH3, benzyl, and phenyl;
R3, at each occurrence, is selected from H, C1-4 alkyl, and phenyl;
A is a C5-6 carbocyclic residue substituted with 0-2 R4;
R4, at each occurrence, is selected from H, xe2x95x90O, (CH2)rOR2, F, Cl, Br, I, C1-4 alkyl, xe2x80x94CN, NO2, (CH2)rNR2R2a, (CH2)rC(O)R2c, NR2C(O)R2b, C(O)NR2R2a, SO2NR2R2a, S(O)pR5, and CF3;
R5, at each occurrence, is selected from CF3, C1-6 alkyl, phenyl, and benzyl;
p, at each occurrence, is selected from 0, 1, and 2; and,
r, at each occurrence, is selected from 0, 1, 2, and 3.
[10] In another still more preferred embodiment, the present invention provides a compound wherein:
Ln is *CH(Ra)NHC(O)CH2;
R is H;
Ra is C(O)C(O)OH;
Z is selected from CH2, (CH2)2C(O), and CH2S(O)2;
A is cyclohexyl or phenyl and is substituted with 0-1 R4;
R4, at each occurrence, is selected from H, xe2x95x90O, OR2, CH2OR2, F, Cl, Br, I, C1-4 alkyl, xe2x80x94CN, NO2, (CH2)rNR2R2a, (CH2)rC(O)R2c, C(O)NR2R2a, SO2NR2R2a, and CF3;
r, at each occurrence, is selected from 0, 1, 2, and 3.
[11] In another even more preferred embodiment, the present invention provides a compound of formula: 
Ln is *CH2NHC(O)CH2 or *CH(Ra)NHC(O)CH2, the * indicates where Ln is bonded to G;
R is H or NH2; 
Ra is C(O)C(O)OR3;
Z is C1-4 alkylene;
R2, at each occurrence, is selected from H, C1-6 alkyl, benzyl, and phenyl;
R2a, at each occurrence, is selected from H, C1-6 alkyl, benzyl, and phenyl;
R2b, at each occurrence, is selected from H. C1-6 alkyl, benzyl, and phenyl;
R2c, at each occurrence, is selected from OH, OCH3, OCH2CH3, CH3, benzyl, and phenyl;
R3, at each occurrence, is selected from H, C1-4 alkyl, and phenyl;
A is phenyl substituted with 0-2 R4;
R4, at each occurrence, is selected from H, (CH2)rOR2, F, Cl, Br, I, C1-4 alkyl, xe2x80x94CN, NO2, (CH2)rNR2R2a, (CH2)rC(O)R2c, NR2C(O)R2b, C(O)NR2R2a, SO2NR2R2a, S(O)pR5, and CF3;
R5, at each occurrence, is selected from CF3, C1-6 alkyl, phenyl, and benzyl;
p, at each occurrence, is selected from 0, 1, and 2; and,
r, at each occurrence, is selected from 0, 1, 2, and 3.
[12] In another still more preferred embodiment, the present invention provides a compound wherein:
Ln is *CH(Ra)NHC(O)CH2;
R is NH2;
Ra is C(O)C(O)OH;
Z is CH2;
A is phenyl substituted with 0-1 R4;
R4, at each occurrence, is selected from H, OR2, CH2OR2, F, Cl, Br, C1-4 alkyl, xe2x80x94CN, NO2, (CH2)rNR2R2a, (CH2)rC(O)R2c, C(O)NR2R2a, SO2NR2R2a, and CF3; and,
r, at each occurrence, is selected from 0, 1, and 2.
[13] In another even more preferred embodiment, the present invention provides a compound of formula: 
Ln is *CH2NHC(O) or *CH(Ra)NHC(O) and the * indicates where Ln is bonded to G;
Ra is selected from C(O)C(O)OR3 and C(O)-A;
Rb is selected from H, phenyl, C1-10 alkyl, and C2-5 alkenyl;
Rc is selected from H and C1-6 alkyl;
alternatively, Rb and Rc together are xe2x80x94(CH2)4xe2x80x94;
Z is (CR8R9)1-4;
R2, at each occurrence, is selected from H, CF3, and C1-6 alkyl;
R2a, at each occurrence, is selected from H, CF3, and C1-6 alkyl;
R2b, at each occurrence, is selected from H, CF3, and C1-6 alkyl;
R2c, at each occurrence, is selected from OH, OCH3, OCH2CH3, CH3, benzyl, and phenyl;
R3, at each occurrence, is selected from H, C1-4 alkyl, and phenyl;
A is selected from:
C6-10 aromatic carbocyclic residue substituted with 0-2 R4, and
5-10 membered aromatic heterocyclic system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-2 R4;
R4, at each occurrence, is selected from H, (CH2)rOR2, F, Cl, Br, I, C1-4 alkyl, xe2x80x94CN, NO2, (CH2)rNR2R2a, (CH2)rC(O)R2c, NR2C(O)R2b, C(O)NR2R2a, SC2NR2R2a, S(O)pR5, and CF3;
R5, at each occurrence, is selected from CF3, C1-6 alkyl, phenyl, and benzyl;
R8, at each occurrence, is selected from H, C1-6 alkyl and phenyl;
R9, at each occurrence, is selected from H, C1-6 alkyl and phenyl;
p, at each occurrence, is selected from 0, 1, and 2;
r, at each occurrence, is selected from 0, 1, 2, and 3.
[14] In another still more preferred embodiment, the present invention provides a compound wherein:
Ln is *CH(Ra)NHC(O) and the * indicates where Ln is bonded to G;
Ra is C(O)C(O)OH or C(O)-(benzothiazol-2-yl);
Rb is selected from H, phenyl, C1-10 alkyl, and C2-5 alkenyl;
Rc is selected from H and C1-6 alkyl;
alternatively, Rb and Rc together are xe2x80x94(CH2)4xe2x80x94;
Z is (CR8H)1-2;
A is selected from phenyl, naphthyl, and thienyl, and A is substituted with 0-1 R4;
R4, at each occurrence, is selected from H, OR2, CH2OR2, F, Cl, Br, I, C1-4 alkyl, xe2x80x94CN, NO2, (CH2)rNR2R2a, (CH2)rC(O)R2c, C(O)NR2R2a, SO2NR2R2a, and CF3;
R8, at each occurrence, is selected from H, methyl and phenyl; and,
r, at each occurrence, is selected from 0, 1, and 2.
[15] In another even more preferred embodiment, the present invention provides a compound of formula: 
Ln is *CH2NHC(O) or *CH(Ra)NHC(O) and the * indicates where Ln is bonded to G;
Ra is selected from C(O)C(O)OR3 and C(O)-A;
Rb is selected from H, phenyl, C1-10 alkyl, and C2-5 alkenyl;
Rc is selected from H and C1-6 alkyl;
alternatively, Rb and Rc together are xe2x80x94(CH2)4xe2x80x94;
R is selected from H, benzyl, C1-4 alkyl, and NH2;
Z is (CR8R9)1-4;
R2, at each occurrence, is selected from H, CF3, and C1-6 alkyl;
R2a at each occurrence, is selected from H, CF3, and C1-6 is alkyl;
R2b, at each occurrence, is selected from H, CF3, and C1-6 alkyl;
R2c, at each occurrence, is selected from OH, OCH3, OCH2CH3, CH3, benzyl, and phenyl;
R3, at each occurrence, is selected from H, C1-4 alkyl, and phenyl;
A is selected from:
C6-10 aromatic ring substituted with 0-2 R4, and
5-10 membered aromatic heterocyclic system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-2 R4;
R4, at each occurrence, is selected from H, (CH2)rOR2, F, Cl, Br, I, C1-4 alkyl, xe2x80x94CN, NO2, (CH2)rNR2R2a, (CH2)rC(O)R2c, NR2C(O)R2b, C(O)NR2R2a, SO2NR2R2a, S(O)pR5, and CF3;
R5, at each occurrence, is selected from CF3, C1-6 alkyl, phenyl, and benzyl;
R8, at each occurrence, is selected from H, C1-6 alkyl and phenyl;
R9, at each occurrence, is selected from H, C1-6 alkyl and phenyl;
p, at each occurrence, is selected from 0, 1, and 2;
r, at each occurrence, is selected from 0, 1, 2, and 3.
[16] In another still more preferred embodiment, the present invention provides a compound wherein:
Ln is *CH(Ra)NHC(O) and the * indicates where Ln is bonded to G;
Ra is C(O)C(O)OH or C(O)-(benzothiazol-2-yl);
Rb is selected from H, phenyl, C1-10 alkyl, and C2-5 alkenyl;
Rc is selected from H and C1-6 alkyl;
alternatively, Rb and Rc together are xe2x80x94(CH2)4xe2x80x94;
Z is (CR8H)1-2;
A is selected from phenyl, naphthyl, and thienyl, and A is substituted with 0-1 R4;
R4, at each occurrence, is selected from H. OR2, CH2OR2, F, Cl, Br, I, C1-4 alkyl, xe2x80x94CN, NO2, (CH2)rNR2R2a, (CH2)rC(O)R2c, C(O)NR2R2a, SO2NR2R2a, and CF3;
R8, at each occurrence, is selected from H. C1-6 alkyl and phenyl;
r, at each occurrence, is selected from 0, 1, and 2.
[17] In another even more preferred embodiment, the present invention provides a compound of formula: 
Ln is *CH2NHC(O) or *CH(Ra)NHC(O) and the * indicates where Ln is bonded to G;
R1a is selected from xe2x80x94(CH2)rxe2x80x94R1xe2x80x2 and NHCH2R1xe2x80x3;
R1xe2x80x2 is selected from H, OR2, NR2R2a, and NR2SO2(CH2)rR2b;
R1xe2x80x3 is selected from C(O)NR2R2a, S(O)2R2b, and SO2NR2R2a;
R2, at each occurrence, is selected from H, C1-6 alkyl, benzyl, and phenyl;
R2a, at each occurrence, is selected from H, C1-6 alkyl, benzyl, and phenyl;
R2b, at each occurrence, is selected from C1-4 alkoxy, C1-6 alkyl, benzyl, phenyl substituted with 0-2 R4b, and 5-6 membered heterocyclic system containing from 1-2 heteroatoms selected from the group consisting of N, O, and S substituted with 0-2 R4b;
R2c, at each occurrence, is selected from OH, OCH3, OCH2CH3, CH3, benzyl, and phenyl;
alternatively, R2 and R2a, together with the atom to which they are attached, combine to form a 5 or 6 membered saturated, partially saturated or unsaturated ring substituted with 0-2 R4b and containing from 0-1 additional heteroatoms selected from the group consisting of N, O, and S;
R3, at each occurrence, is selected from H, C1-4 alkyl, and phenyl;
A is phenyl substituted with 0-2 R4;
A1 is H or A;
alternatively, A and A1 and the carbon to which they are attached combine to form fluorene;
A2 is selected from H, A, and CHA3A4;
A3 is selected from H, A, C1-4 alkyl, and xe2x80x94(CH2)rNR2R2a;
A4 is H or A;
R4, at each occurrence, is selected from H, (CH2)rOR2, F, Cl, Br, I, C1-4 alkyl, xe2x80x94CN, NO2, (CH2)rNR2R2a, (CH2)rC(O)R2c, NR2C(O)R2b, C(O)NR2R2a, SO2NR2R2a, S(O)pR5, and CF3;
R4b, at each occurrence, is selected from H, (CH2)rOR2, F, Cl, Br, I, C1-4 alkyl, xe2x80x94CN, NO2, (CH2)rNR2R2a, (CH2)rC(O)R2c, NR2C(O)R2b, C(O)NR2R2a, SO2NR2R2a, S(O)pR5, and CF3;
R5, at each occurrence, is selected from CF3, C1-6 alkyl, phenyl, and benzyl;
p, at each occurrence, is selected from 0, 1, and 2;
r, at each occurrence, is selected from 0, 1, 2, and 3.
[18] In another still more preferred embodiment, the present invention provides a compound wherein:
Ln is *CH2NHC(O) and the * indicates where Ln is bonded to G;
R1a is selected from xe2x80x94(CH2)rxe2x80x94R1xe2x80x2 and NHCH2R1xe2x80x3;
R1xe2x80x2 is selected from OH, NR2R2a, and NR2SO2(CH2)rR2b;
R1xe2x80x3 is selected from C(O)NR2R2a, S(O)2R2b, and SO2NR2R2a;
R2, at each occurrence, is selected from H, C1-6 alkyl, benzyl, and phenyl;
R2a, at each occurrence, is selected from H, C1-6 alkyl, benzyl, and phenyl;
R2b, at each occurrence, is selected from C1-4 alkoxy, C1-6 alkyl, benzyl, phenyl substituted with 0-1 R4b, and pyrrolidinyl substituted with 0-1 R4b;
R2c, at each occurrence, is selected from OH, OCH3, OCH2CH3, CH3, benzyl, and phenyl;
alternatively, R2 and R2a, together with the atom to which they are attached, combine to form a piperidine ring substituted with 0-1 R4b;
R4, at each occurrence, is selected from H, xe2x95x90O, OR2, CH2OR2, F, Cl, Br, I, C1-4 alkyl, xe2x80x94CN, NO2, (CH2)rNR2R2a, (CH2)rC(O)R2c, C(O)NR2R2a, SO2NR2R2a, and CF3;
R4b, at each occurrence, is selected from H, xe2x95x90O, OH, F, Cl, C1-4 alkyl, and NH2; and,
r, at each occurrence, is selected from 0, 1, and 2.
[19] In another even more preferred embodiment, the present invention provides a compound of formula: 
Ln is O or S;
M2 is N or CRf;
M3 is N or CRd;
provided that only one of M2 and M3 is N;
Re is selected from H, N(CH3)(CH2CO2H) and S-(5-6 membered aromatic heterocyclic system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-2 R4);
Rd is selected from H, F and Cl;
alternatively, Rd and Re combine to form xe2x80x94NR3xe2x80x94C(O)xe2x80x94C(R1bR3)xe2x80x94NR3xe2x80x94 or xe2x80x94Nxe2x95x90CR2xe2x80x94NR3xe2x80x94;
Rf is selected from H, F, and Cl;
alternatively, Re and Rf combine to form xe2x80x94NR3xe2x80x94C(R1bR3)xe2x80x94C(O)xe2x80x94NR3xe2x80x94 or xe2x80x94NR3xe2x80x94CR2xe2x95x90Nxe2x80x94;
Z is O, provided that Z does not form a Nxe2x80x94O or NCH2O bond with the groups to which Z is attached;
R1b is selected from H, C1-6 alkyl, and C1-6 alkyl substituted with A;
R2, at each occurrence, is selected from H, C1-6 alkyl, benzyl, and phenyl;
R2a, at each occurrence, is selected from H, C1-6 alkyl, benzyl, and phenyl;
R2b, at each occurrence, is selected from H, C1-6 alkyl, benzyl, and phenyl;
R2c, at each occurrence, is selected from OH, OCH3, OCH2CH3, CH3, benzyl, and phenyl;
R3, at each occurrence, is selected from H, C1-4 alkyl, and phenyl;
A is selected from:
C5-6 carbocyclic residue substituted with 0-2 R4, and
5-6 membered heterocyclic system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-2 R4;
B is H or Y;
Y is selected from:
C5-6 carbocyclic residue substituted with 0-2 R4a, and
5-6 membered heterocyclic system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-2 R4a;
R4, at each occurrence, is selected from H, xe2x95x90O, (CH2)rOR2, F, Cl, Br, I, C1-4 alkyl, xe2x80x94CN, NO2, (CH2)rNR2R2a, (CH2)rC(O)R2c, NR2C(O)R2b, C(O)NR2R2a, C(xe2x95x90NR2)NR2R2a, NHC(xe2x95x90NR2) NR2R2a, SO2NR2R2a, and CF3;
R4a, at each occurrence, is selected from H, xe2x95x90O, (CH2)rOR2, (CH2)rxe2x80x94F, (CH2)rxe2x80x94Br, (CH2)rxe2x80x94Cl, Cl, Br, F, I, C1-4 alkyl, xe2x80x94CN, NO2, (CH2)rNR2R2a, (CH2)rC(O)R2c, NR2C(O)R2b, C(O)NR2R2a, C(xe2x95x90NR2)NR2R2a, NHC(xe2x95x90NR2)NR2R2a, SO2NR2R2a, and CF3; and,
r, at each occurrence, is selected from 0, 1, 2, and 3.
[20] In another still more preferred embodiment, the present invention provides a compound wherein:
Ln is O;
Re is N(CH3)(CH2CO2H);
Rd is H or F;
alternatively, Rd and Re combine to form xe2x80x94NR3xe2x80x94C(O)xe2x80x94C(R1bR3)xe2x80x94NR3xe2x80x94 or xe2x80x94Nxe2x95x90CR2xe2x80x94NR3xe2x80x94;
Rf is H or F;
alternatively, Re and Rf combine to form xe2x80x94NR3xe2x80x94C(R1bR3)xe2x80x94C(O)xe2x80x94NR3xe2x80x94 or xe2x80x94NR3xe2x80x94CR2xe2x95x90Nxe2x80x94;
R1b is selected from H, C1-2 alkyl and benzyl;
A is phenyl substituted with 0-2 R4;
B is H or Y;
Y is 5 membered heterocyclic system containing from 1-2 heteroatoms selected from the group consisting of N, O, and S substituted with 0-2 R4a;
R4, at each occurrence, is selected from H, C1-4 alkyl, and NR2R2a; and,
R4a, at each occurrence, is selected from H, C1-4 alkyl, and NR2R2a.
[21] In another even more preferred embodiment, the present invention provides a compound of formula: 
Ln is *CH2NHC(O)CH2 or *CH(Ra)NHC(O)CH2 and the * indicates where Ln is bonded to G;
M1 is absent or is CHR;
R is selected from H, Cl, F, Br, I, OR3, C1-4 alkyl, OCF3, CF3, and NH2;
Z is C1-4 alkylene;
R2, at each occurrence, is selected from H, C1-6 alkyl, benzyl, and phenyl;
R2a, at each occurrence, is selected from H, C1-6 alkyl, benzyl, and phenyl;
R2c, at each occurrence, is selected from OH, OCH3, OCH2CH3, CH3, benzyl, and phenyl;
R3, at each occurrence, is selected from H, C1-4 alkyl, and phenyl;
A is selected from:
C3-6 carbocyclic residue substituted with 0-2 R4, and
5-6 membered aromatic heterocyclic system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-2 R4;
R4, at each occurrence, is selected from H, (CH2)rOR2, F, Cl, Br, I, C1-4 alkyl, (CH2)rNR2R2a, (CH2)rC(O)R2c, C(O)NR2R2a, SO2NR2R2a, and CF3; and,
r, at each occurrence, is selected from 0, 1, 2, and 3.
[22] In another still more preferred embodiment, the present invention provides a compound wherein:
Ln is *CH2NHC(O)CH2 and the * indicates where Ln is bonded to G.;
M1 is absent;
R is selected from H and C1-4 alkyl;
Z is CH2;
A is C3-6 carbocyclic residue substituted with 0-1 R4;
R4, at each occurrence, is selected from H, C1-4 alkyl, (CH2)rNR2R2a, and CF3; and,
r, at each occurrence, is selected from 0, 1, and 2.
[23] In another even more preferred embodiment, the present invention provides a compound of formula: 
Ln is absent;
R2, at each occurrence, is selected from H, C1-6 alkyl, benzyl, and phenyl;
R2a, at each occurrence, is selected from H, C1-6 alkyl, benzyl, and phenyl;
R2c, at each occurrence, is selected from OH, OCH3, OCH2CH3, CH3, benzyl, and phenyl;
X is SO2 or SO2(CHxe2x95x90CH);
Y is selected from:
C6-10 carbocyclic residue substituted with 0-2 R4a, and
5-6 membered aromatic heterocyclic system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-2 R4a;
R4, at each occurrence, is selected from H, xe2x95x90O, OR2, CH2OR2, F, Cl, Br, I, C1-4 alkyl, (CH2)rNR2R2a, (CH2)rC(O)R2c, C(O)NR2R2a, SO2NR2R2a, and CF3;
R4a, at each occurrence, is selected from H, OR2, CH2OR2, F, Cl, Br, I, C1-4 alkyl, (CH2)rNR2R2a, (CH2)rC(O)R2c, C(O)NR2R2a, SO2NR2R2a, and CF3; and,
r, at each occurrence, is selected from 0, 1, 2, and 3.
[24] In another still more preferred embodiment, the present invention provides a compound wherein:
X is SO2;
Y is selected from phenyl substituted with 0-2 R4a and naphthyl substituted with 0-2 R4a;
R4, at each occurrence, is selected from H, xe2x95x90O, OH, CH2OH, F, Cl, Br, C1-4 alkyl, C(O)NR2R2a, and C(O)R2c;
R4a, at each occurrence, is selected from H, OH, CH2OH, F, Cl, Br, C1-4 alkyl, and C(O)R2c; and,
r, at each occurrence, is selected from 0, 1, and 2.
[25] In another even more preferred embodiment, the present invention provides a compound of formula: 
Ln is absent;
R2, at each occurrence, is selected from H. C1-6 alkyl, benzyl, and phenyl;
R2a, at each occurrence, is selected from H, C1-6 alkyl, benzyl, and phenyl;
R2c, at each occurrence, is selected from OH, OCH3, OCH2CH3, CH3, benzyl, and phenyl;
alternatively, R2 and R2a, together with the atom to which they are attached, combine to form a 5 or 6 membered saturated, partially saturated or unsaturated ring and containing from 0-1 additional heteroatoms selected from the group consisting of N. O, and S;
X is SO2 or SO2(CHxe2x95x90CH);
Y is selected from:
C6-10 carbocyclic residue substituted with 0-2 R4a, and
5-6 membered aromatic heterocyclic system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-2 R4a;
R4, at each occurrence, is selected from H, xe2x95x90O, OR2, CH2OR2, F, Cl, Br, I, C1-4 alkyl, (CH2)rNR2R2a, (CH2)rC(O)R2c, C(O)NR2R2a, SO2NR2R2a, and CF3;
R4a, at each occurrence, is selected from H, OR2, CH2OR2, F, Cl, Br, I, C1-4 alkyl, (CH2)rNR2R2a, (CH2)rC(O)R2c, C(O)NR2R2a, SO2NR2R2a, and CF3;
r, at each occurrence, is selected from 0, 1, 2, and 3.
[26] In another still more preferred embodiment, the present invention provides a compound wherein:
X is SO2;
Y is phenyl substituted with 0-2 R4a or naphthyl substituted with 0-2 R4a;
R4, at each occurrence, is selected from H, xe2x95x90O, OR2, CH2OR2, F, Cl, Br, I, C1-4 alkyl, NH2, (CH2)rC(O)R2c, and C(O)NR2R2a;
R4a, at each occurrence, is selected from H, xe2x95x90O, OR2, CH2OR2, F, Cl, Br, I, C1-4 alkyl, NH2, (CH2)rC(O)R2c, and C(O)NR2R2a;
r, at each occurrence, is selected from 0, 1, 2, and 3.
[27] In another even more preferred embodiment, the present invention provides a compound of formula: 
Ln is absent;
R2, at each occurrence, is selected from H, C1-6 alkyl, benzyl, and phenyl;
R2a, at each occurrence, is selected from H, C1-6 alkyl, benzyl, and phenyl;
R2c, at each occurrence, is selected from OH, OCH3, OCH2CH3, CH3, benzyl, and phenyl;
alternatively, R2 and R2a, together with the atom to which they are attached, combine to form a 5 or 6 membered saturated, partially saturated or unsaturated ring and containing from 0-1 additional heteroatoms selected from the group consisting of N, O, and S;
X is SO2 or SO2(CHxe2x95x90CH);
Y is selected from:
C6-10 carbocyclic residue substituted with 0-2 R4a, and
5-6 membered aromatic heterocyclic system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-2 R4a;
R4, at each occurrence, is selected from H, xe2x95x90O, OR2, CH2OR2, F, Cl, Br, I, C1-4 alkyl, (CH2)rNR2R2a, (CH2)rC(O)R2c, C(O)NR2R2a, SO2NR2R2a, and CF3;
R4a, at each occurrence, is selected from H, OR2, CH2OR2, F, Cl, Br, I, C1-4 alkyl, (CH2)rNR2R2a, (CH2)rC(O)R2c, C(O)NR2R2a, SO2NR2R2a, and CF3;
r, at each occurrence, is selected from 0, 1, 2, and 3.
[28] In another still more preferred embodiment, the present invention provides a compound wherein:
X is SO2;
Y is phenyl substituted with 0-2 R4a or naphthyl substituted with 0-2 R4a;
R4, at each occurrence, is selected from H, xe2x95x90O, OR2, CH2OR2, F, Cl, Br, I, C1-4 alkyl, NH2, (CH2)rC(O)R2c, and C(O)NR2R2a;
R4a, at each occurrence, is selected from H, R2, CH2OR2, F, Cl, Br, I, C1-4 alkyl, NH2, (CH2)rC(O) R2c, and C(O)NR2R2a; and,
r, at each occurrence, is selected from 0, 1, and 2.
[29] In another even more preferred embodiment, the present invention provides a compound of formula: 
Ra is C(O)-(6 membered heterocyclic system containing 1 N atom and substituted with 0-2 R4);
R2, at each occurrence, is selected from H, C1-6 alkyl, benzyl, and phenyl;
R2a, at each occurrence, is selected from H, C1-6 alkyl, benzyl, and phenyl;
R2c, at each occurrence, is selected from OH, OCH3, OCH2CH3, CH3, benzyl, and phenyl;
alternatively, R2 and R2a, together with the atom to which they are attached, combine to form a 5 or 6 membered saturated, partially saturated or unsaturated ring and containing from 0-1 additional heteroatoms selected from the group consisting of N, O, and S;
A is a 10 membered bicyclic heterocyclic system containing 1 N atom and substituted with 0-2 R4;
B is H or Y;
Y is selected from:
C3-6 carbocyclic residue substituted with 0-2 R4a, and
5-6 membered aromatic heterocyclic system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-2 R4a;
R4, at each occurrence, is selected from H, xe2x95x90O, OR2, F, Cl, Br, I, C1-4 alkyl, NR2R2a, (CH2)rC(O)R2c, C(O)NR2R2a, and CF3;
R4a, at each occurrence, is selected from H, xe2x95x90O, OR2, F, Cl, Br, I, C1-4 alkyl, NR2R2a, (CH2)rC(O)R2c, C(O)NR2R2a, and CF3;
r, at each occurrence, is selected from 0, 1, 2, and 3.
[30] In a still more preferred embodiment, the present invention provides a compound wherein:
Ra is C(O)xe2x80x94(N-1,2,3,6-tetrahydropyridine substituted with CO2H);
alternatively, Ra is C(O)xe2x80x94(N-1,2,3,6-tetrahydropyridine substituted with CH3);
A is 1,2,3,4-tetrahydroisoquinoline substituted with 1-2 R4;
B is H;
R4, at each occurrence, is selected from H, methyl, xe2x95x90O, OR2, F, Cl, Br, I, C1-4 alkyl, NR2R2a, (CH2)rC(O)R2c, C(O)NR2R2a, SO2NR2R2a, and CF3;
r, at each occurrence, is selected from 0, 1, and 2.
[31] In another even more preferred embodiment, the present invention provides a compound of formula: 
R2, at each occurrence, is selected from H, C1-6 alkyl, benzyl, and phenyl;
R2a, at each occurrence, is selected from H, C1-6 alkyl, benzyl, and phenyl;
R2c, at each occurrence, is selected from OH, OCH3, OCH2CH3, CH3, benzyl, and phenyl;
alternatively, R2 and R2a, together with the atom to which they are attached, combine to form a 5 or 6 membered saturated, partially saturated or unsaturated ring and containing from 0-1 additional heteroatoms selected from the group consisting of N, O, and S;
X iS OSO2;
Y is selected from:
C6-10 aromatic ring substituted with 0-2 R4a, and
5-10 membered aromatic heterocyclic system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-2 R4a;
R4 is H;
R4a, at each occurrence, is selected from H, (CH2)rOR2, F, Cl, Br, I, C1-4 alkyl, xe2x80x94CN, (CH2)rNR2R2a, (CH2)rC(O)R2c, C(O)NR2R2a, SO2NR2R2a, and CF3; and,
r, at each occurrence, is selected from 0, 1, 2, and 3.
[32] In a still more preferred embodiment, the present invention provides a compound wherein:
R is methyl;
Y is selected from phenyl substituted with 0-2 R4a, naphtyl substituted with 0-2 R4a, and quinolinyl substituted with 0-2 R4a;
R4a, at each occurrence, is selected from H, (CH2)rOR2, F, Cl, Br, I, C1-4 alkyl, (CH2)rNR2R2a, and CF3; and,
r, at each occurrence, is selected from 0, 1, and 2.
[33] In another more preferred embodiment, the present invention provides a compound of formula: 
Rg is selected from H, CH2OR3, CH2C(O)OR3, C1-4 alkyl, C(O)NH2, and NH2;
Rh is selected from H, CH2-phenyl, CH2CH2-phenyl, and CHxe2x95x90CH-phenyl;
R2, at each occurrence, is selected from H, C1-6 alkyl, benzyl, and phenyl;
R2a, at each occurrence, is selected from H, C1-6 alkyl, benzyl, and phenyl;
R2c, at each occurrence, is selected from OH, OCH3, OCH2CH3, CH3, benzyl, and phenyl;
alternatively, R2 and R2a, together with the atom to which they are attached, combine to form a 5 or 6 membered saturated, partially saturated or unsaturated ring and containing from 0-1 additional heteroatoms selected from the group consisting of N, O, and S;
R3, at each occurrence, is selected from H, C1-4 alkyl, and phenyl;
A is selected from:
C6-10 aromatic ring substituted with 0-2 R4, and
5-6 membered aromatic heterocyclic system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-2 R4;
B is H or Y;
Y is selected from:
C6-10 aromatic ring substituted with 0-2 R4a, and
5-6 membered aromatic heterocyclic system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-2 R4a;
R4, at each occurrence, is selected from H, (CH2)rOR2, F, Cl, Br, I, C1-4 alkyl, xe2x80x94CN, (CH2)rNR2R2a, (CH2)rC(O)R2c, S(O)NR2R2a, SO2NR2R2a, S(O)pR5, and CF3;
R4a, at each occurrence, is selected from H, (CH2)rOR2, Cl, Br, F, I, C1-4 alkyl, xe2x80x94CN, (CH2)rNR2R2a, (CH2)rC(O)R2c, C(O)NR2R2a, SO2NR2R2a, S(O)pR5, and CF3;
R5, at each occurrence, is selected from CF3, C1-6 alkyl, phenyl, and benzyl;
p, at each occurrence, is selected from 0, 1, and 2; and,
r, at each occurrence, is selected from 0, 1, 2, and 3.
[34] In a still more preferred embodiment, the present invention provides a compound wherein:
Rg is selected from CH2OR3, and CH2C(O)OCH3;
Rh is selected from CH2-phenyl, CH2CH2-phenyl, and CHxe2x95x90CH-phenyl;
A is phenyl;
B is Y;
Y is phenyl substituted with 0-2 R4a;
R4a, at each occurrence, is selected from H, OR2, Cl, Br, F, I, C1-4 alkyl, (CH2)rNR2R2a, C(O)NR2R2a, and CF3; and,
r, at each occurrence, is selected from 0, 1, and 2.
[35] In another more preferred embodiment, the present invention provides a compound of formula: 
Ri is selected from SO2CH2C(O)OR3, C(O)CH2C(O)OR3, and C(O)OR3;
X is O;
Y is pyrrolidinyl substituted with 1-2 R4a or piperidinyl substituted with 1-2 R4a;
R2, at each occurrence, is selected from H, C1-6 alkyl, benzyl, and phenyl;
R2a, at each occurrence, is selected from H, C1-6 alkyl, benzyl, and phenyl;
alternatively, R2 and R2a, together with the atom to which they are attached, combine to form a 5 or 6 membered saturated, partially saturated or unsaturated ring and containing from 0-1 additional heteroatoms selected from the group consisting of N, O, and S;
R3, at each occurrence, is selected from H, C1-4 alkyl, and phenyl;
R4, at each occurrence, is selected from H, F, Cl, Br, I, C1-4 alkyl, NR2R2a, and CF3; and,
R4a, at each occurrence, is selected from H, C1-4 alkyl, CH2NR2R2a, and C(xe2x95x90NR2)CH3.
[36] In a still more preferred embodiment, the present invention provides a compound wherein:
Ri is selected from SO2CH2C(O)OR3 and C(O)CH2C(O)OR3;
Y is piperidinyl substituted with 1-2 R4a;
R3, at each occurrence, is selected from H and C1-4 alkyl;
R4 is H; and,
R4a, at each occurrence, is selected from H, C1-4 alkyl, CH2NR2R2a, and C(xe2x95x90NR2)CH3.
In another more preferred embodiment, the present invention provides a compound of formula: 
Ri is selected from SO2CH2C(O)OR3, C(O)CH2C(O)OR3, and C(O)OR3;
X is O;
Y is pyrrolidinyl substituted with 1-2 R4a or piperidinyl substituted with 1-2 R4a;
R2 at each occurrence, is selected from H, C1-6 alkyl, benzyl, and phenyl;
R2a, at each occurrence, is selected from H, C1-6 alkyl, benzyl, and phenyl;
alternatively, R2 and R2a, together with the atom to which they are attached, combine to form a 5 or 6 membered saturated, partially saturated or unsaturated ring and containing from 0-1 additional heteroatoms selected from the group consisting of N, O, and S;
R3, at each occurrence, is selected from H, C1-4 alkyl, and phenyl;
R4, at each occurrence, is selected from H, F, Cl, Br, I, C1-4 alkyl, NR2R2a, and CF3; and,
R4a, at each occurrence, is selected from H, C1-4 alkyl, CH2NR2R2a, and C(xe2x95x90NR2)CH3.
In a still more preferred embodiment, the present invention provides a compound wherein:
Ri is selected from SO2CH2C(O)OR3 and C(O)CH2C(O)OR3;
Y is piperidinyl substituted with 1-2 R4a;
R3, at each occurrence, is selected from H and C1-4 alkyl;
R4 is H; and,
R4a, at each occurrence, is selected from H, C1-4 alkyl, CH2NR2R2a, and C(xe2x95x90NR2)CH3.
In a second embodiment, the present invention provides compounds selected from the group: 
or a stereoisomer or pharmaceutically acceptable salt thereof, wherein;
G is selected from: 
Ra is selected from C(O)C(O)OH and C(O)(benzothiazol-2-yl);
Rg is selected from H, CH2OR3, CH2C(O)OR3, C1-4 alkyl, C(O)NH2, and NH2;
Rh is selected from H, CH2-phenyl, CH2CH2-phenyl, and CHxe2x95x90CH-phenyl;
Ri is selected from SO2CH2C(O)OH and C(O)CH2C(O)OH, and C(O)OR3;
R, at each occurrence, is selected from H, methyl, ethyl, benzyl, and NH2;
R2, at each occurrence, is selected from H, CF3, CH3, benzyl, and phenyl;
R2a, at each occurrence, is selected from H, CF3, CH3, benzyl, and phenyl;
alternatively, R2 and R2a combine to form a ring system selected from pyrrolidinyl, piperazinyl and morpholino;
R3, at each occurrence, is selected from H, C1-4 alkyl, and phenyl;
Z is C(O)CH2 or CONH;
A is selected from phenyl, pyridyl, and pyrimidyl, and is substituted with 0-2 R4; and,
B is selected from Y, Xxe2x80x94Y, phenyl, pyrrolidino, morpholino, 1,2,3-triazolyl, and imidazolyl, and is substituted with 0-1 R4a;
R4, at each occurrence, is selected from OH, (CH2)rOR2, halo, C1-4 alkyl, (CH2)rNR2R2a, and (CF2)rCF3;
R4a is selected from C1-4 alkyl, CF3, S(O)2R5, SO2NR2R2a, and 1-CF3-tetrazol-2-yl;
R5, at each occurrence, is selected from CF3, C1-6 alkyl, phenyl, and benzyl;
X is CH2 or C(O);
Y is selected from NR2R2a and CH2NR2R2a;
p is selected from 0, 1, and 2; and,
r is selected from 0, 1, and 2.
In another embodiment, the present invention provides novel pharmaceutical compositions, comprising: a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of present invention or a pharmaceutically acceptable salt form thereof.
In another embodiment, the present invention provides a novel method for treating or preventing a thromboembolic disorder, comprising: administering to a patient in need thereof a therapeutically effective amount of a compound of the present invention or a pharmaceutically acceptable salt form thereof.
The compounds herein described may have asymmetric centers. Compounds of the present invention containing an asymmetrically substituted atom may be isolated in optically active or racemic forms. It is well known in the art how to prepare optically active forms, such as by resolution of racemic forms or by synthesis from optically active starting materials. Many geometric isomers of olefins, Cxe2x95x90N double bonds, and the like can also be present in the compounds described herein, and all such stable isomers are contemplated in the present invention. Cis and trans geometric isomers of the compounds of the present invention are described and may be isolated as a mixture of isomers or as separated isomeric forms. All chiral, diastereomeric, racemic forms and all geometric isomeric forms of a structure are intended, unless the specific stereochemistry or isomeric form is specifically indicated. All processes used to prepare compounds of the present invention and intermediates made therein are considered to be part of the present invention.
xe2x80x9cSubstitutedxe2x80x9d is intended to indicate that one or more hydrogens on the atom indicated in the expression using xe2x80x9csubstitutedxe2x80x9d is replaced with a selection from the indicated group(s), provided that the indicated atom""s normal valency is not exceeded, and that the substitution results in a stable compound. When a substituent is keto (i.e., xe2x95x90O) group, then 2 hydrogens on the atom are replaced.
The present invention is intended to include all isotopes of atoms occurring in the present compounds. Isotopes include those atoms having the same atomic number but different mass numbers. By way of general example and without limitation, isotopes of hydrogen include tritium and deuterium. Isotopes of carbon include C-13 and C-14.
When any variable (e.g., R6) occurs more than one time in any constituent or formula for a compound, its definition at each occurrence is independent of its definition at every other occurrence. Thus, for example, if a group is shown to be substituted with 0-2 R6, then said group may optionally be substituted with up to two R6 groups and R6 at each occurrence is selected independently from the definition of R6. Also, combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.
When a bond to a substituent is shown to cross a bond connecting two atoms in a ring, then such substituent may be bonded to any atom on the ring. When a substituent is listed without indicating the atom via which such substituent is bonded to the rest of the compound of a given formula, then such substituent may be bonded via any atom in such substituent. Combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.
As used herein, xe2x80x9calkylxe2x80x9d or xe2x80x9calkylenexe2x80x9d is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms. C1-10 alkyl (or alkylene), is intended to include C1, C2, C3, C4, C5, C6, C7, C8, C9, and C10 alkyl groups. Examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, t-butyl, n-pentyl, and s-pentyl. xe2x80x9cHaloalkylxe2x80x9d is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms, substituted with 1 or more halogen (for example xe2x80x94CvFw where v=1 to 3 and w=1 to (2v+1)). Examples of haloalkyl include, but are not limited to, trifluoromethyl, trichloromethyl, pentafluoroethyl, and pentachloroethyl. xe2x80x9cAlkoxyxe2x80x9d represents an alkyl group as defined above with the indicated number of carbon atoms attached through an oxygen bridge. C1-10 alkoxy, is intended to include C1, C2, C3, C4, C5, C6, C7, C8, C9, and C10 alkoxy groups. Examples of alkoxy include, but are not limited to, methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, s-butoxy, t-butoxy, n-pentoxy, and s-pentoxy. xe2x80x9cCycloalkylxe2x80x9d is intended to include saturated ring groups, such as cyclopropyl, cyclobutyl, or cyclopentyl. C3-7 cycloalkyl, is intended to include C3, C4, C5, C6, and C7 cycloalkyl groups. xe2x80x9cAlkenylxe2x80x9d or xe2x80x9calkenylenexe2x80x9d is intended to include hydrocarbon chains of either a straight or branched configuration and one or more unsaturated carbonxe2x80x94carbon bonds which may occur in any stable point along the chain, such as ethenyl and propenyl. C2-10 alkenyl (or alkenylene), is intended to include C2, C3, C4, C5, C6, C7, C8, C9, and C10 alkenyl groups. xe2x80x9cAlkynylxe2x80x9d or xe2x80x9calkynylenexe2x80x9d is intended to include hydrocarbon chains of either a straight or branched configuration and one or more triple carbonxe2x80x94carbon bonds which may occur in any stable point along the chain, such as ethynyl and propynyl. C2-10 alkynyl (or alkynylene), is intended to include C2, C3, C4, C5, C6, C7, C8, C9, and C10 alkynyl groups.
xe2x80x9cHaloxe2x80x9d or xe2x80x9chalogenxe2x80x9d as used herein refers to fluoro, chloro, bromo, and iodo; and xe2x80x9ccounterionxe2x80x9d is used to represent a small, negatively charged species such as chloride, bromide, hydroxide, acetate, and sulfate.
As used herein, xe2x80x9ccarbocyclexe2x80x9d or xe2x80x9ccarbocyclic groupxe2x80x9d is intended to mean any stable 3, 4, 5, 6, or 7-membered monocyclic or bicyclic or 7, 8, 9, 10, 11, 12, or 13-membered bicyclic or tricyclic, any of which may be saturated, partially unsaturated, or aromatic. Examples of such carbocycles include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, adamantyl, cyclooctyl, [3.3.0]bicyclooctane, [4.3.0]bicyclononane, [4.4.0]bicyclodecane, [2.2.2]bicyclooctane, fluorenyl, phenyl, naphthyl, indanyl, adamantyl, and tetrahydronaphthyl.
As used herein, the term xe2x80x9cheterocyclexe2x80x9d or xe2x80x9cheterocyclic groupxe2x80x9d is intended to mean a stable 5, 6, or 7-membered monocyclic or bicyclic or 7, 8, 9, or 10-membered bicyclic heterocyclic ring which is saturated, partially unsaturated or unsaturated (aromatic), and which consists of carbon atoms and 1, 2, 3, or 4 heteroatoms independently selected from the group consisting of N, NH, O and S and including any bicyclic group in which any of the above-defined heterocyclic rings is fused to a benzene ring. The nitrogen and sulfur heteroatoms may optionally be oxidized. The heterocyclic ring may be attached to its pendant group at any heteroatom or carbon atom which results in a stable structure. The heterocyclic rings described herein may be substituted on carbon or on a nitrogen atom if the resulting compound is stable. A nitrogen in the heterocycle may optionally be quaternized. It is preferred that when the total number of S and O atoms in the heterocycle exceeds 1, then these heteroatoms are not adjacent to one another. It is preferred that the total number of S and O atoms in the heterocycle is not more than 1. As used herein, the term xe2x80x9caromatic heterocyclic groupxe2x80x9d or xe2x80x9cheteroarylxe2x80x9d is intended to mean a stable 5, 6, or 7-membered monocyclic or bicyclic or 7, 8, 9, or 10-membered bicyclic heterocyclic aromatic ring which consists of carbon atoms and 1, 2, 3, or 4 heterotams independently selected from the group consisting of N, NH, O and S. It is to be noted that total number of S and O atoms in the aromatic heterocycle is not more than 1.
Examples of heterocycles include, but are not limited to, acridinyl, azocinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzthiazolyl, benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolinyl, carbazolyl, 4aH-carbazolyl, carbolinyl, chromanyl, chromenyl, cinnolinyl, decahydroquinolinyl, 2H, 6H-1,5,2-dithiazinyl, dihydrofuro[2,3-b]tetrahydrofuran, furanyl, furazanyl, imidazolidinyl, imidazolinyl, imidazolyl, 1H-indazolyl, indolenyl, indolinyl, indolizinyl, indolyl, 3H-indolyl, isobenzofuranyl, isochromanyl, isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl, isothiazolyl, isoxazolyl, methylenedioxyphenyl, morpholinyl, naphthyridinyl, octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl, oxazolyl, oxazolidinyl, pyrimidinyl, phenanthridinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl, phthalazinyl, piperazinyl, piperidinyl, piperidonyl, 4-piperidonyl, piperonyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridooxazole, pyridoimidazole, pyridothiazole, pyridinyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, 2H-pyrrolyl, pyrrolyl, quinazolinyl, quinolinyl, 4H-quinolizinyl, quinoxalinyl, quinuclidinyl, tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, tetrazolyl, 6H-1,2,5-thiadiazinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thianthrenyl, thiazolyl, thienyl, thienothiazolyl, thienooxazolyl, thienoimidazolyl, thiophenyl, triazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl, and xanthenyl. Also included are fused ring and spiro compounds containing, for example, the above heterocycles.
The phrase xe2x80x9cpharmaceutically acceptablexe2x80x9d is employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
As used herein, xe2x80x9cpharmaceutically acceptable saltsxe2x80x9d refer to derivatives of the disclosed compounds wherein the parent compound is modified by making acid or base salts thereof. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like. The pharmaceutically acceptable salts include the conventional non-toxic salts or the quaternary ammonium salts of the parent compound formed, for example, from non-toxic inorganic or organic acids. For example, such conventional non-toxic salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric and the like; and the salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isethionic, and the like.
The pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound which contains a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, nonaqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred. Lists of suitable salts are found in Remington""s Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., 1985, p. 1418, the disclosure of which is hereby incorporated by reference.
xe2x80x9cProdrugsxe2x80x9d are intended to include any covalently bonded carriers which release the active parent drug according to formula (I) in vivo when such prodrug is administered to a mammalian subject. Prodrugs of a compound of formula (I) are prepared by modifying functional groups present in the compound in such a way that the modifications are cleaved, either in routine manipulation or in vivo, to the parent compound. Prodrugs include compounds of formula (I) wherein a hydroxy, amino, or sulfhydryl group is bonded to any group that, when the prodrug or compound of formula (I) is administered to a mammalian subject, cleaves to form a free hydroxyl, free amino, or free sulfhydryl group, respectively. Examples of prodrugs include, but are not limited to, acetate, formate and benzoate derivatives of alcohol and amine functional groups in the compounds of formula (I), and the like.
xe2x80x9cStable compoundxe2x80x9d and xe2x80x9cstable structurexe2x80x9d are meant to indicate a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent.
xe2x80x9cTherapeutically effective amountxe2x80x9d is intended to include an amount of a compound of the present invention or an amount of the combination of compounds claimed effective to inhibit factor Xa or thrombin or treat diseases related to factor Xa or thrombin in a host. The combination of compounds is preferably a synergistic combination. Synergy, as described for example by Chou and Talalay, Adv. Enzyme Regul. 22:27-55 (1984), occurs when the effect (in this case, inhibition of factor Xa or thrombin) of the compounds when administered in combination is greater than the additive effect of the compounds when administered alone as a single agent. In general, a synergistic effect is most clearly demonstrated at suboptimal concentrations of the compounds. Synergy can be in terms of lower cytotoxicity, increased antiviral effect, or some other beneficial effect of the combination compared with the individual components.
The compounds of the present invention can be prepared in a number of ways known to one skilled in the art of organic synthesis. The compounds of the present invention can be synthesized using the methods described below, together with synthetic methods known in the art of synthetic organic chemistry, or by variations thereon as appreciated by those skilled in the art. Preferred methods include, but are not limited to, those described below. The reactions are performed in a solvent appropriate to the reagents and materials employed and suitable for the transformations being effected. It will be understood by those skilled in the art of organic synthesis that the functionality present on the molecule should be consistent with the transformations proposed. This will sometimes require a judgment to modify the order of the synthetic steps or to select one particular process scheme over another in order to obtain a desired compound of the invention. It will also be recognized that another major consideration in the planning of any synthetic route in this field is the judicious choice of the protecting group used for protection of the reactive functional groups present in the compounds described in this invention. An authoritative account describing the many alternatives to the trained practitioner is Greene and Wuts (Protective Groups In Organic Synthesis, Wiley and Sons, 1991). All references cited herein are hereby incorporated in their entirety herein by reference. 
Compounds of the above formulas can be prepared by coupling corresponding acid and amine precursors. The acid precursors can be prepared as shown in WO98/28326, WO 98/09987, WO/28326, WO96/19483, and WO98/05333, the contents of which are incorporated herein by reference. The G-CH(Ra)NH2 precursors can be prepared as shown in the above-identified publications or as shown in the present application. 
Compounds of the above formulas can be prepared by coupling corresponding acid and amine precursors. The acid precursors can be prepared as shown in WO98/05333, the contents of which are incorporated herein by reference. The G-CH(Ra)NH2 precursors can be prepared as shown in the above-identified publications or as shown in the present application. 
Compounds of the above formula can be prepared by coupling the corresponding acid and amine precursors. The acid precursors can be prepared as shown in U.S. Pat. No. 5,798,377, the contents of which are incorporated herein by reference. The G-CH2NH2 precursors can be prepared as shown in the above-identified publication or as shown in the present application. 
Compounds of the above formula can be prepared by coupling corresponding G-leaving group and alcohol-pyridyl or thiol-pyridyl precursors. The alcohol and thio precursors can be prepared as shown in U.S. Pat. No. 5,693,641, WO96/28427, WO97/29067, WO98/07725, and WO98/15547, the contents of which are incorporated herein by reference. The G-leaving group precursors can be prepared as shown in the above-identified publications or as shown in the present application. Alternatively, the compounds of the above formula can be prepared by displacing a leaving group from the pyridyl precursor with the corresponding G-OH precursor. Leaving groups for this type of coupling can be SCH3 or SO2CH3. 
Compounds of the above formula can be prepared by coupling corresponding acid and amine precursors. The acid precursors can be prepared as shown in WO98/17274, the contents of which are incorporated herein by reference. The G-CH2NH2 precursors can be prepared as shown in the above-identified publication or as shown in the present application. 
Compounds of the above formula can be prepared by coupling corresponding G-benzoic acid and piperazine precursors. The G-benzoic acid precursors can be prepared similarity to the methods shown in WO98/21188, the contents of which are incorporated herein by reference. For example, the G-benzoic acid precursors can be prepared by coupling an activated G (e.g., a metallated ring) with a leaving group-benzoic acid (e.g., halo-benzoic acid) as shown in the above-identified publication. The piperazine precursors can be prepared by coupling of the desired piperazine with the desired Xxe2x80x94Y group, wherein X contains a leaving group, as shown in the above-identified application or in the present application. 
Compounds of the above formulas can be prepared by coupling corresponding benzoic acid and piperazine precursors. The G-piperidinyl acid or G-piperazinyl acid precursors can be prepared similarity to the methods shown in WO96/10022, the contents of which are incorporated herein by reference. For example, the G-piperidinyl acid or G-piperazinyl acid precursors can be prepared by coupling a G-leaving group (e.g., G-halogen) with a piperidinyl acid or piperazinyl acid as shown in the above-identified publication. The piperidine and piperazine precursors can be prepared by coupling of the desired piperazine with the desired Xxe2x80x94Y group, wherein X contains a leaving group, as shown in the above-identified application or in the present application. 
Compounds of the above formula can be prepared by coupling corresponding sulfonic acid and amine precursors. The sulfonic acid precursors can be prepared as shown in WO96/33993, the contents of which are incorporated herein by reference. The G-CH2CH(Ra)NH2 precursors can be prepared as shown in the above-identified publication or as shown in the present application. 
Compounds of the above formula can be prepared by coupling corresponding G-CHO or G-CH2Br and (Rg)CH2CH2(Rh)N(R3)C(O)-A-B precursors. The (Rg)CH2CH2(Rh)N(R3)C(O)-A-B precursors can be prepared as shown in WO97/24118, the contents of which are incorporated herein by reference. The G-CHO and G-CH2Br precursors can be prepared as shown in the above-identified publication or as shown in the present application. 
Compounds of the above formula can be prepared by coupling corresponding G-(CH2)3-leaving group and ester precursors. The ester precursors can be prepared as shown in EP/0540051, the contents of which are incorporated herein by reference. The G-(CH2)3-leaving group precursors can be prepared as shown in the above-identified publication or other publications described herein or as shown in the present application.
Compounds of the above formula when G contains an amine linker can be prepared by displacing a leaving group off of the remainder of the molecule with corresponding G-amine precursor. The remainder of the molecule can be prepared as shown in JP10/1467, the contents of which are incorporated herein by reference. The G-NH2 precursors can be prepared as shown in the above-identified publications or as shown in the present application. 
Compounds of the above formula can be prepared by coupling corresponding G-(CH2)3-leaving group and phenol precursors. The phenol precursors can be prepared as shown in WO97/36580, the contents of which are incorporated herein by reference or as shown in the present application. The G-(CH2)3-leaving group precursors can be prepared as shown in the above-identified publication or other publications described herein or as shown in the present application. 
Compounds of the above formulas can be prepared by coupling corresponding aniline and G-(CH2)3-leaving group or G-(CH2)2CO2H precursors. The aniline precursors can be prepared as shown in EP/0540051, JP10/1467, and WO96/16940, the contents of which are incorporated herein by reference. The G-(CH2)3-leaving group or G-(CH2)2CO2H precursors can be prepared as shown in the above-identified publication or other publications described herein or as shown in the present application.
Many of the compounds of the present invention can be prepared from G-NH2 where G represents a residue which is either the P1 residue described above, a suitably protected form of the P1 residue, or an intermediate which can be transformed at a later stage of the synthesis into the P1 residue. Scheme I describes procedures by which the amino residue of G-NH2 can be transformed into a variety of different functionalities which are useful for assembling the compounds of the present invention. G-NH2 I can be diazotized with sodium nitrite in the presence of aqueous sulfuric acid to produce the hydroxy derivative II. Diazotization of I in acidic media followed by treatment with copper (I) bromide affords the bromo derivative III. The bromo derivative is a very useful intermediate for further functionalization. Treatment of III with magnesium metal generates a Grignard reagent which can react with suitably protected bromoglycinate derivatives to afford amino acid derivatives IV. There are a wide variety of methods available for introducing simple carbon-atom based functionality starting with bromide III. Transmetallation with an organolithium reagent such as tert-butyllithium or n-butyllithium is readily accomplished at low temperature. The formed organolithium species can react with a wide variety of electrophiles. For example, reaction with dimethylformamide produces the aldehyde derivative V, while reaction with an alkyl chloroformate or an alkyl cyanoformate produces an ester derivative. The ester functionality can be reduced with a variety of hydride reducing agents such as lithium aluminum hydride or diisobutylaluminum hydride to afford the alcohol VI. The alcohol VI can also be prepared by reduction of aldehyde V, such as with sodium borohydride. The bromide III can also react through palladium-mediated processes. For example, reaction of III with an alcohol or amine and a catalyst such as tetrakis-triphenylphosphine palladium under a carbon monoxide atmosphere leads to esters G-CO2R or amides G-CONR2 via a carbonyl insertion reaction. A particularly useful amide G-CONR2 available by this procedure is the N-methyl-N-methoxy amide, obtained when N-methyl-N-methoxyamine is used in the carbonyl insertion reaction. This amide is readily reduced to aldehyde V with hydride reducing agents such as diisobutylaluminum hydride. The alcohol VI, readily available by a variety of methods as described above can be converted to the bromide derivative VII by many methods, such as by treatment with carbon tetrabromide and triphenylphosphine. Another method for the preparation of bromide VII, not shown in Scheme I, involves the radical bromination of an intermediate G-CH3, which is readily available by methods known to those skilled in the art of organic synthesis. This radical bromination is readily accomplished by treating G-CH3 with N-bromosuccinimide in refluxing carbon tetrachloride in the presence of a radical initiator such as AIBN. The bromide VII is a particularly useful intermediate for the preparation of the compounds of the present invention. Displacement of the bromide can be accomplished by treatment with sodium or potassium cyanide in a solvent such as DMF or DMSO at room temperature or elevated temperature to give a cyano derivative. Reduction of the nitrile, such as by catalytic hydrogenation or by treatment with sodium borohydride and cobalt (II) chloride, gives the amino derivative VIII. The bromide can also be displaced by appropriate N-protected glycinates, such as N-(diphenylmethylene)glycine ethyl ester, to give the amino acid derivatives IX. This reaction is accomplished by heating VII and the glycinate in the presence of a base such as potassium carbonate and a quaternary ammonium salt such as tetrabutylammonium bromide in a solvent such as acetonitrile. The bromide can also be displaced with sodium azide in a solvent such as DMF or DMSO at elevated temperatures to give an azide intermediate. The azide is readily reduced by a variety of reducing agents, such as by catalytic hydrogenation or by tin (II) chloride, to afford the amino derivative XI. A variety of other methods are available for the preparation of the amino derivative XI. For example, reductive amination of aldehyde V with ammonium acetate and sodium cyanoborohydride affords XI. Alternatively, the amine G-NH2 I can be diazotized as described above and reacted with copper (I) cyanide to afford the nitrile X. The nitrile can be reduced to form amine XI by a variety of methods, such as by catalytic hydrogenation or by reduction with sodium borohydride in the presence of cobalt (II) chloride. A variety of other methods for the preparation of the intermediates described in Scheme I are available and are known to those skilled in the art. The particular method used for the preparation of the required intermediates will depend on additional functionality present on group xe2x80x9cGxe2x80x9d, and it will be appreciated by those skilled in the art that certain protecting group strategies may be required and that reaction conditions and the order of steps may require modification. 
The compound wherein G is a 2,5-bis(aminomethyl)phenyl group can be prepared from commercially available amino-terephthalate as shown in the Scheme II below. 
The amino group can be further manipulated as described in Scheme I above.
Scheme III describes the preparation of mono-protected 2-methylaminoaniline intermediates. 
The following are some examples of conditions required for selective protection of the benzylamine functionality.
The mono-protected 2-methylaminoaniline intermediates required to make the 2-methylaminophenyl analogs of this invention can be prepared from the known anthranilic acids by the route outlined in Scheme IV. The anthranilic acid is simultaneously reduced to the benzyl alcohol and N-protected by formation of the mixed anhydride/N-carbamoyl compound followed by selective reduction of the anhydride functionality with aqueous sodium borohydride.
The benzylalcohol is then transformed to the benzylazide by a two-step sequence involving methanesulfonate ester formation followed by displacement of the sulfonate ester with sodium azide in dimethylformamide. The 2-methylaminoaniline can be obtained from the benzylazide by removal of the carbamoyl group with ethanolic sodium hydroxide followed by catalytic reduction of the azide group.
Representitive methods for the selective protection of the more reactive benzylamine functionality with a few of the protecting groups (-P.G.) that may be contemplated for the realization of this invention are illustrated in the above table.
Scheme IV describes the preparation of 1,4-disubstituted-6-aminophthalazine intermediates. 
Synthesis of 1,4-disubstituted-6-aminophthalazines in which the 1 and 4-positions may be a protected amine could be accomplished starting from the commercially available 3,4-dicyanonitrobenzene. Addition of hydrazine to bis-nitrile would form the phthalazine core. Suitable protection and reduction of the aryl nitro group would provide the desired compound.
Scheme V describes the preparation of 6-amino-2-aminoquinoline intermediates. 
Scheme VI describes the preparation of 7-amino-2-aminoquinoline intermediates. 
Scheme VII describes the preparation of 6-aminoquinazoline intermediates. 
Synthesis of 6-aminoquinazolines in which the 2-position may be a hydrogen, a protected amine, or an alkyl group and the 4-position is a protected amine could be accomplished starting from commercially available 3-cyano-4-fluoronitrobenzene. Reaction of guanidine or amidine nucleophiles at the nitrile followed by fluorine displacement to ring closure would yield the quinazoline core (J. Heterocyclic Chem., 1991, 28, 1357). Suitable protection and reduction of the aryl nitro group would provide the title compound.
Scheme VIII describes the preparation of 7-aminoquinazoline intermediates. 
Synthesis of 7-aminoquinazolines in which the 2-position may be a hydrogen, a protected amine, or an alkyl group and the 4-position is a protected amine could be accomplished starting from commercially available 2-fluoro-4-nitrobenzoic acid. Conversion of carboxylic acid to nitrile via standard manipulations would give 2-fluoro-4-nitrobenzonitrile. Reaction of guanidine or amidine nucleophiles at the nitrile followed by fluorine displacement to ring closure would yield the quinazoline core (J. Heterocyclic Chem., 1991, 28, 1357). Suitable protection and reduction of the aryl nitro group would provide the 7-aminoquinazoline.
Scheme IX describes the preparation of 7-aminoisoquinazoline intermediates. 
Synthesis of 7-aminoisoquinolines in which the 1 or 4-position may be a protected amine could be accomplished from the corresponding known 7-nitroisoquinoline by published methods (see for example, U.S. Pat. No. 4,673,676). Suitable protection and reduction of the aryl nitro group would provide the 7-aminoisoquinoline.
Scheme X describes the preparation of 6-aminoisoquinazoline intermediates. 
Synthesis of 6-aminoisoquinolines in which the 1 or 4-position may be a protected amine could be accomplished starting from commercially available 1,2,3,4-tetrahydroisoquinoline. Conversion to the known 6-nitro isoquinoline (Chem. Pharm. Bull. 1958, 6, 497, 499) and on to the 1- and 4-amino derivatives (see for example U.S. Pat. No. 4,673,676) followed by suitable protection and reduction of the aryl nitro group would provide the desired compound.
Scheme XI describes the preparation of 7-aminophthalazine intermediates. 
Synthesis of 7-aminophthalazines in which the 1-position may be a protected amine could be accomplished starting from commercially available 2-cyano-4-nitrotoluene. Bromination of tolyl methyl to give a benzyl bromide followed by displacement with hydrazine would afford benzyl hydazine intermediate. Ring closure by subsequent addition to the nitrile under thermal conditions would yield the phthalazine core. Suitable protection and reduction of the aryl nitro group would provide the desired compound.
Scheme XII describes the preparation of 6-aminophthalazine intermediates. 
Synthesis of 6-aminophthalazines in which the 1-position may be a protected amine could be accomplished starting from commercially available 2-bromo-5-nitrotoluene. Displacement of bromide with cyanide followed by bromination of tolyl methyl will give a benzyl bromide. Displacement of bromide with hydrazine would afford benzyl hydazine intermediate suitable for ring closure by subsequent addition to the nitrile under thermal conditions to yield the phthalazine core. Suitable protection and reduction of the aryl nitro group would provide the title compound.
The A-B moieties of the present can be prepared by methods known to those of skill in the art. The A-B moieties of the present can be prepared by methods described in the above-identified publications. For example, the following publications, the contents of which are incorporated herein by reference, describe and exemplify means of preparing A-B moieties: WO97/23212, WO97/30971, WO98/06694, WO98/01428, WO98/28269, and WO98/28282.
Other features of the invention will become apparent in the course of the following descriptions of exemplary embodiments which are given for illustration of the invention and are not intended to be limiting thereof.